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VOL. 73 (4), 901-925, 2007 ROLES OF PROTEIN PHOSPHATASE TYPE 1...

PP1 AND ISOFORMS

In humans, Protein Phosphatases Type 1 are encoded by three
highly related genes (PP1a, PP1ß/d and PP1?) and alternative splicing
generates the ?1 and ?2 isoforms. With the exception of S. cerevi-
siae, which has one PP1 gene, all eukaryotes have multiple genes
with 8 in A. thaliana, 4 in D. melanogaster and a predicted 30 in
C. elegans (13).

Although the cytosolic forms of mammalian PP1, such as those
targeted to glycogen and myosin, have been studied in greatest detail,
a PP1 activity enriched in the nucleus. The significance of the
different PP1 isoforms remains unclear; however, in vivo data show
that they have distinct subcellular localization patterns (14, 15). All
isoforms are found in the nucleus in interphase cells, with PP1? and
PP1ß/d showing additional accumulations in nucleoli. PP1 isoforms
localization patterns are also dynamic and change both through the
cell cycle and in response to various cellular perturbations. It is
important to note that global patterns of localization that are
observed for each isoform represent the sum of many different PP1-
targeting subunit complexes, as shown by the immunostaining of
several nuclear targeting subunits with overlapping localization
patterns. The distinct localization patterns of the PP1 isoforms
therefore imply difference in the specificity of interaction with
particular targeting subunits, and so preferential incorporation into
different signalling complexes.

It is commonly assumed among enzymologists that the substrate
specificity of an enzyme is determined primarily by sterochemical
complementarity between a substrate and the active site. The
multiplicity of localizations and functions in the case of PP1 suggest
that the preference for a phosphorylated sequence in the different
protein substrates is not very stringent and does not explain in vivo
specicificity. PP1 has evolved effective catalytic machinery but lacks
strong substrate specificity in its active site. PP1 finds its targets via
a large number of regulatory subunits, which influence the activity,
and cellular localization of the phosphatase (Figure 1B) (16). To
date, more than 50 PP1-protein interactions have been identified (6,
17, 18). With few exceptions so far, PP1 associates with its targeting
subunits through the small motif RVXF. Co-crystallization of PP1

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